Modeling Cardiomyopathy of Duchenne Muscular Dystrophy in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Abstract/Contents
- Abstract
- Duchenne muscular dystrophy (DMD) is a lethal, genetic myopathy caused by mutations in the dystrophin gene that lead to loss of muscle function and culminate in early adulthood death due to cardiorespiratory failure. While treatment options for the respiratory effects of DMD have improved, there remain limited treatment options for DMD cardiomyopathy. In addition, researchers lack an understanding of the biophysical disease mechanisms underlying the cardiac dysfunction in DMD patients. The development of new therapeutics and research on this mechanism have been hampered by the lack of an appropriate animal or cell model for the cardiac phenotypes of DMD. In the last several years, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a potent means of investigating both treatments for and the underlying mechanisms of DMD cardiomyopathy. Accordingly, I used a hiPSC-CM platform to investigate the effects of Tamoxifen, a selective estrogen receptor modulator that alleviates DMD symptoms in skeletal muscle. Treatment with Tamoxifen decreased beating rate, increased beating velocity, and prolonged cellular functional longevity of DMD hiPSC-CMs. These findings suggest Tamoxifen can counteract the tachycardia, the decreased left ventricular ejection fraction, and the loss of cardiomyocyte function observed in DMD patients. In addition, in this thesis, I describe a novel computational analysis system that uses traction force microscopy and live-cell cytoskeletal staining imaging to provide a holistic understanding of cardiomyocyte contraction. Upon applying this system to DMD hiPSC CMs, I found that dystrophin mutations impair cardiomyocyte function principally by reducing cytoskeletal contraction. This research demonstrates the effectiveness of a bioengineered hiPSC-CM platform to model the cardiac phenotypes of DMD. Additionally, it highlights the potential of Tamoxifen, a novel therapeutic in overcoming arrythmia, and provides new insights into the understanding of the biophysical mechanisms that drive DMD cardiomyopathy, informing future therapeutic development.
Description
| Type of resource | text |
|---|---|
| Date created | June 2021 |
| Date modified | December 5, 2022 |
| Publication date | May 3, 2022 |
Creators/Contributors
| Author | Birnbaum, Foster |
|---|---|
| Degree granting institution | Stanford University, Department of Biology, 2021 |
| Thesis advisor | Blau, Helen |
| Thesis advisor | Gozani, Or |
| Thesis advisor | Wu, Joseph |
Subjects
| Subject | Stanford University Department of Biology |
|---|---|
| Subject | Duchenne muscular dystrophy |
| Subject | Human induced pluripotent stem cell-derived cardiomyocyte |
| Subject | Tamoxifen |
| Subject | Traction force microscopy |
| Subject | Single sarcomere dynamics |
| Subject | Biomechanics |
| Subject | Bioengineering |
| Genre | Text |
| Genre | Thesis |
Bibliographic information
Access conditions
- Use and reproduction
- User agrees that, where applicable, content will not be used to identify or to otherwise infringe the privacy or confidentiality rights of individuals. Content distributed via the Stanford Digital Repository may be subject to additional license and use restrictions applied by the depositor.
- License
- This work is licensed under a Creative Commons Attribution Share Alike 3.0 Unported license (CC BY-SA).
Preferred citation
- Preferred citation
- Birnbaum, Foster; Blau, Helen; Gozani, Or; and Wu, Joseph. (2021). Modeling Cardiomyopathy of Duchenne Muscular Dystrophy in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Stanford Digital Repository. Available at https://purl.stanford.edu/qp023js4198
Collection
Undergraduate Theses, Department of Biology, 2020-2021
View other items in this collection in SearchWorksContact information
- Contact
- fosb@stanford.edu
Also listed in
Loading usage metrics...